The structural integrity of the myocardial cells is crucial for cell function during myocardial ischemia and drug therapy. Alterations in the myocardial sarcolemma and mitochondria are prime events in the genesis of an irreversible cell injury where Ca is intimately associated with the injury. In order to characterize structural changes in ischemia and anoxia and their prevention by specific pharmacological agents, both isolated rat hearts and in vivo animal models will be employed. The main objectives of this study are: to characterize morphological changes in the hydrophobic region of sarcolemma during anoxia with fluctuations of ions, especially Ca, Na, K; to determine structural changes in junctional and non-junctional sarcolemma in ischemic myocardium before and after treatment with the Ca channel blockers, propranolol and glucose-insulin-potassium; to quantitate changes in in vitro anoxic and in vivo ischemic cyocardium and to correlate them with blood flow, ATP and Ca content and loss of CPK before and after therapy; and to determine if combination therapy can maximize the effect on dying cells. We have demonstrated that depletion of Ca ions disrupts the cell junctions and gap junctions. This structural change is completely prevented by hypothermia and Ca channel blockers. It is hypothesized that preservation of Ca in the hydrophobic region of sarcolemma is essential for stability of bilayer phospholipids and glycoproteins, and Ca channel blockers further prevent influx of Ca during Ca paradox and reperfusion of ischemic myocardium. We will investigate the therapeutic effects of Ca channel blockers individually or in combination with other agents that may prevent ischemic injury. Finally, quantitative ultrastructural data from ischemic and anoxic hearts with or without drugs will be correlated with biochemical data and elemental contents and blood flow in order to evaluate and interpret the results in a physiological setting.